Key events in B lymphocyte formation, including the expression of relevant transcription factors, assembly of receptor complexes and elimination of autoreactive cells, are being defined at an increasing pace. Simultaneously, numerous molecules expressed in the bone marrow microenvironment with the potential to regulate this process have also been identified. However the key players in this regulation have been difficult to determine, since in many cases the same factors are described as either agonists or antagonists of lymphocyte generation. The investigator has completed studies recently that indicate that estrogen and other sex steroids can play an important role in the steady state regulation of B lymphopoiesis. B-cell precursors were severely depressed in pregnant or estrogen-treated mice, whereas they were elevated in hormone-deficient animals. It appears that bone marrow stromal cells produce an inhibitor of lymphopoiesis in response to estrogen and so studies are proposed to characterize and identify this agent. Further studies are proposed to identify other modulating agents that can act alone or together with hormones to affect survival, expansion and differentiation of B-cell precursors. Assays will also be developed that allow extension of these studies in the mouse system to analysis with human cells. Finally, an attempt will be made to devise new culture systems that support the growth and differentiation of very early progenitor populations under carefully defined conditions. These studies may reveal how hormone levels can influence: 1) the regeneration of B-cells following transplantation or chemotherapy; 2) the growth of B lineage tumors; and 3) the course of autoimmune diseases. Thus information generated in these studies directly relevant to women's health issues, age-related studies, the consequences of hormone therapy, to immunodeficiencies, to autoimmune diseases and to endocrine abnormalities.